DNA-scaffolded biomaterials enable modular and tunable control of - PowerPoint PPT Presentation

The 16 th US-Korea Forum on Nanotechnology DNA-scaffolded biomaterials enable modular and tunable control of immune cell therapies Xiao Huang, PhD Postdoc Scholar, Desai Lab University of California San Francisco

CAR-T therapy – revolutionary cancer therapy CANCER CELL CD19 CAR T CELL Brown & Mackall. Nature Reviews Immunology, 2019

Efficacy and safety are critical aspects for cancer therapy On-tumor efficacy Off-tumor safety Lim & June. Cell, 2017

Biomaterials can modulate immune cell behaviors Immune cell EFFICACY SAFETY engaging particles (ICEp) Regulatory P signals NORMAL TUMOR TUMOR ON Riley, et al. Nature Reviews Drug Discovery, 2019

DNA scaffolds on biomaterials allows efficient loading and precise control of functional proteins FAST VERSATILE R strand : G strand : B strand Input 3:1:1 Input 1:1:1 Input 1:1:3 ATGCGCTACATGCTCTC RT 2 mins 5 𝛎 m Unmatch Match EFFICIENT microparticles (nM/OD550) 25 ≅ IgG loading on PLGA Theoretical 20 Footprint Limit 15 10 5 0 l a n o DNA- DNA- DNA- i t i d Low Medium High a r T

ICEp can provide unique opportunities for boosting of immune cell efficacy Human T P Co-stimulatory signals primary T Cytokines cells Checkpoint inhibitors ICEp- 𝛃 -CD3/ 𝛃 - Adjuvants CD3/CD28 CD28 Antigens … CD4+ T CD8+ T 3.2 × 10 7 P = 0.0115 CD4+ T cell number at day 14 CD8+ T cell number at day 14 4 × 10 7 2.8 × 10 7 P = 0.0153 2.5 × 10 7 2.4 × 10 7 2.0 × 10 7 2.0 × 10 7 1.5 × 10 7 1.6 × 10 7 1.0 × 10 7 1.2 × 10 7 5.0 × 10 6 1 × 10 7 2 × 10 6 5 × 10 6 day 0 = 0 0 [1:5] [1:3] [1:1] [3:1] [5:1] 1.4x10 5 [1:5] [1:3] [1:1] [3:1] [5:1]

Local activation of AND-gate CAR-T cells by ICEp to enhance safety % Target killing by CD8+ T 80 P 60 TF 40 Traditional chemistry CAR 20 0 No ICEp GFP density 1. Roybal, et al. Cell, 2016 2. Huang, et al. BioRxiv, 2019

NSG mice dual tumor model for local CAR-T cell activation SynNotch CAR-T Untransduced T 2400 2400 P = 0.0075 Without ICEp P = 0.5166 Tumor volume (mm 3 ) (n=8) (n = 8) With ICEp 1800 1800 P = P = 0.3092 0.0032 P = 0.6595 (n=8) (n=6) 1200 1200 (n = 8) 600 600 0 0 4 8 12 16 4 8 12 16 Day after T cell injection Huang, et al. BioRxiv, 2019

Acknowledgements Dr. Tejal Desai Dr. Ryan Chang Zhongbo Li Desai lab members Dr. Wendell Lim Dr. Jasper Williams Dr. Wei Yu Dr. David Patterson Thank you! PBBR